Share This

In a study that could lead to new therapeutic targets for patients with the cystic fibrosis, a research team from the University of California, San Diego School of Medicine has identified a defective signaling pathway that contributes to disease severity. In the study, published in the journal Nature Medicine, the researchers report that defective signaling for a protein called the peroxisome proliferator-activated receptor-γ (PPAR-γ) accounts for a portion of disease symptoms in cystic fibrosis, and that correction of the defective pathway reduces symptoms of the disease in mice.

Related Articles

In the paper published in the February 14 edition of the journal, lead investigator Gregory Harmon, MD, study supervisor Christopher Glass, MD, PhD, professor of cellular and molecular medicine, and colleagues show that both mice and cells from patients with cystic fibrosis have a defect in signaling for PPAR-γ, as a result of reduced levels of prostaglandins that activate the receptor.

Cystic fibrosis is the most common, potentially lethal genetic disease among whites, occurring in one in 3,000 births. The disease is a multisystem condition that leads to progressive lung failure, pancreatic failure and gastrointestinal obstruction, or blockage.

"Cystic fibrosis results from a genetic mutation in a channel, or membrane pore, that facilitates the transport of chloride and bicarbonate electrolytes from inside the cell to the spaces outside the cell," said Harmon. "Loss of the cystic fibrosis pore channel results in inflammation and mucus accumulation. It also results in dehydration of the cell surfaces that make up the lining spaces inside the lungs and other affected organs, such as the intestinal tract."

Exactly how the process occurs has been a matter of intense scientific scrutiny; yet despite numerous therapeutic advances, individuals with the disease continue to endure a shortened lifespan. "Someone born in the 1990s with cystic fibrosis is expected to live to an age of around 40," Harmon added.

Working with isolated cells from mice and human cell lines from patients with the disease, Harmon identified that multiple genes affected by PPAR-γ were reduced in cystic fibrosis. When the researchers treated mice with cystic fibrosis with the drug rosiglitazone, a thiazolidinedione drug that binds and activates PPAR-γ, gene expression was largely normalized and survival improved. The drugs also corrected part of the inflammatory process in the tissue. Deleting the PPAR-γ protein in the intestine of mice worsened the disease, leading to mucus accumulation in the intestine. Additionally, the researchers found that activating PPAR-γ could increase bicarbonate production in the intestinal tissue by increasing the activity of bicarbonate-producing enzymes called carbonic anhydrases.

"For the first time, we are able to use a drug that activates bicarbonate transport without affecting chloride transport, and see improvement in the disease," Harmon said. The results provide support for the hypothesis of experts in the field such as UCSD's Paul Quinton, PhD, who has written that increasing bicarbonate in cystic fibrosis tissues could be a relevant target for future therapies.

"The finding of the reduced PPAR-γ activating prostaglandin in cystic fibrosis is exciting since it could serve as a marker to identify which patients might benefit from treatment with PPAR-&gamm activating drugs," said Glass.

Additional contributors include Darren S. Dumlao and Edward A. Dennis of the Department of Chemistry and Biochemistry and Department of Pharmacology; Damian T. Ng, Department of Cellular and Molecular Medicine; and Kim E. Barrett and Hui Dong, Department of Medicine; all at the University of California, San Diego.

These studies were supported by grants from the National Institutes of Health and a Fellowship to Faculty Transition Award from the Foundation for Digestive Health and Nutrition to Harmon.

More From ScienceDaily

More Health & Medicine News

Featured Research

Mar. 31, 2015  In addition to their physical injuries, women who are victims of domestic violence are also at a greater risk of mental health problems such as depression and psychotic symptoms. "We studied the ... full story

Mar. 31, 2015  New research has scientists re-thinking how a lethal fungus grows and kills immune cells. The study hints at a new approach to therapy for Candida albicans, one of the most common causes of ... full story

Mar. 31, 2015  As the United States faces transplant waiting lists that continue to grow longer over time, there is increasing debate about the proper way to incentivize living donations. Due to organ shortages, ... full story

Mar. 31, 2015  The most virulent strains of Streptococcus suis, the leading cause of bacterial meningitis in adult humans in parts of southeast Asia and in pigs around the world, are likely to have evolved and ... full story

Mar. 31, 2015  A unique pattern of immune molecules in the cerebrospinal fluid of people with myalgic encephalomyelitis/chronic fatigue syndrome have been discovered, providing insights into the basis for cognitive ... full story

Mar. 31, 2015  Children who get a taste of their parents' wine now and then may be more likely than their peers to start drinking by high school, according to a new report. The findings are based on 561 Rhode ... full story

Mar. 31, 2015  Scientists have uncovered the unique mechanism of a powerful natural product with wide-ranging antifungal, antibacterial, anti-malaria and anti-cancer effects. The work sheds light on the natural ... full story

Mar. 30, 2015  Neuroscientists are taking inspiration from natural motor control to design new prosthetic devices that can better replace limb function. Researchers have tested a range of brain-controlled devices ... full story

Mar. 30, 2015  Scientists have found the genetic signature of enterovirus D68 in half of the California and Colorado children diagnosed with acute flaccid myelitis -- sudden, unexplained muscle weakness and ... full story

Mar. 30, 2015  The first study to investigate the relationship between eating fruit and vegetables containing pesticide residues and the quality of men's semen has shown a link with lower sperm counts and ... full story

Featured Videos

Solitair Device Aims to Takes Guesswork out of Sun Safety

Reuters - Innovations Video Online (Mar. 31, 2015)  The Solitair device aims to take the confusion out of how much sunlight we should expose our skin to. Small enough to be worn as a tie or hair clip, it monitors the user&apos;s sun exposure by taking into account their skin pigment, location and schedule. Matthew Stock reports.
Video provided by Reuters

Soda, Salt and Sugar: The Next Generation of Taxes

Washington Post (Mar. 30, 2015)  Denisa Livingston, a health advocate for the Dinι Community Advocacy Alliance, and the Post&apos;s Abby Phillip discuss efforts around the country to make unhealthy food choices hurt your wallet as much as your waistline.
Video provided by Washington Post

S. Leone in New Anti-Ebola Lockdown

AFP (Mar. 28, 2015)  Sierra Leone imposed a three-day nationwide lockdown Friday for the second time in six months in a bid to prevent a resurgence of the deadly Ebola virus. Duration: 01:17
Video provided by AFP

Related Stories

Feb. 18, 2015  Cystic fibrosis mucus actually gets stuck inside some of the cells that create it, rather than simply becoming stuck on the outside linings of organs, researchers have found, which can increase the ... full story

Feb. 18, 2015  Potential targets for therapy for some adolescents with cystic fibrosis who develop advanced liver disease have been found by researchers. They found that those with liver disease had a different ... full story

Oct. 29, 2012  Scientists have established that a drug recently approved by the US Food and Drug Administration to treat a rare form of cystic fibrosis works in an unconventional way. Their results reveal new ... full story

Aug. 1, 2011  The clinical outcome is improved if patients with chronic lung diseases such as cystic fibrosis are treated long-term with the antibiotic azithromycin. However, azithromycin treatment in patients ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.